Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: A phase II randomized clinical trial
Authors: Wen-Kuan Huang, Hung-Chih Hsu, Tsai-Sheng Yang, Chun-Wei Lu, Yi-Ru Pan, Chiao-En Wu, Wen-Hung Chung, Shuen-Iu Hung, Chun-Nan Yeh
Journal: Journal of the American Academy of Dermatology (2023)

This article is being co-published in the Journal of the American Academy of Dermatology and the European Journal of Cancer because it is of critical importance to different readerships. This article was formally reviewed and accepted by Journal of the American Academy of Dermatology before it was approved by the Editor-in-Chief of European Journal of Cancer. The articles in both journals are identical except for minor stylistic and spelling differences in keeping with each journal's style. Either citation can be used when citing this article. To the Editor: Hand-foot skin reaction (HFSR), characterized by skin abnormalities on palmoplantar surfaces, has an overall incidence of about 35% upon vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment.1Ding F. Liu B. Wang Y. Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: a meta-analysis of 57 randomized controlled trials involving 24,956 patients.J Am Acad Dermatol. 2020; 83: 788-796https://doi.org/10.1016/j.jaad.2019.04.021Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Zinc, which plays a role in maintaining skin health, may be involved in the pathogenesis of HFSR.2Nosewicz J. Spaccarelli N. Roberts K.M. et al.The epidemiology, impact, and diagnosis of micronutrient nutritional dermatoses part 1: zinc, selenium, copper, vitamin A, and vitamin C.J Am Acad Dermatol. 2022; 86: 267-278https://doi.org/10.1016/j.jaad.2021.07.079Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Zinc deficiency has been shown to be associated with dermatologic toxicities of epidermal growth factor receptor (EGFR)-TKI.3Tohyama M. Sakaguchi C. Nishina T. Hyodo I. Possible involvement of zinc deficiency in epidermal growth factor receptor inhibitor-induced xerotic dermatitis.J Dermatol. 2021; 48: 1579-1583https://doi.org/10.1111/1346-8138.16049Crossref PubMed Scopus (8) Google Scholar,4Lu C.W. Pang J.S. Ko Y.S. et al.Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.J Eur Acad Dermatol Venereol. 2023; 37: 328-339https://doi.org/10.1111/jdv.18703Crossref PubMed Scopus (6) Google Scholar Regorafenib—an oral multikinase inhibitor targeting VEGFR 1 to 3, PDGFR, cKIT, BRAF, and RET1—is approved for the treatment of metastatic colorectal cancer but commonly causes HFSR.5Grothey A. Van Cutsem E. Sobrero A. et al.Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet. 2013; 381: 303-312https://doi.org/10.1016/S0140-6736(12)61900-XAbstract Full Text Full Text PDF PubMed Scopus (2194) Google Scholar This phase II randomized trial aimed to investigate whether zinc supplementation can reduce the severity of HFSR induced by regorafenib within the first 8 weeks of treatment (NCT03898102). A total of 65 patients with metastatic colorectal cancer were randomly assigned into either zinc supplementation group (32 patients) or control group without zinc supplementation (33 patients) from March 2016 to March 2019. Zinc gluconate was administered orally with a dosage of 78 mg twice daily. This supplementation was continued until the end of study treatment or at the discretion of the investigator. After 4 weeks of regorafenib treatment, both zinc supplementation and control groups had similar incidence of grade 2/3 HFSR (30.3% [10/33] and 21.8% [7/32], respectively). However, after 8 weeks, the proportion of patients with grade 2/3 HFSR significantly decreased from 21.8% to 12.5% (4/32) in the zinc supplementation group, while it increased from 30.3% to 33.3% (11/33) in the control group (P = 0.046) (Fig 1). Median serum zinc concentrations at baseline were similar between zinc supplementation (67.75 μg/dL) and control (65.7 μg/dL) groups. After 4 weeks, there was no significant difference in serum zinc concentrations between the 2 groups. However, after 8 weeks, serum zinc concentrations significantly increased in the zinc supplementation group compared to the control group (Fig 2). Lower median zinc concentration was associated with high-grade (grade ≥ 2) HFSR at week 4 in the control group, but there was no difference in HFSR grade based on zinc concentrations in the zinc supplementation group, suggesting a potential role of zinc deficiency in the pathogenesis of HFSR (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/dw2cwjsc8d/1). During the first 8 weeks of treatment, 64% of patients in the control group and 69% of patients in the zinc supplementation group experienced dose reduction. Both median progression-free survival and overall survival were not different between the zinc supplementation and control groups. Major study limitations include a small sample size, open-label design, lack of data on quality of life, and potential influence of skin care during the study period on the severity of HFSR. However, patients were assigned to the same dermatologist, regardless of the study group, to minimize differences in skin toxicity management. This study demonstrated that zinc supplementation reduced the incidence of grade ≥2 HFSR during regorafenib use, providing a basis for further investigation of zinc supplementation in alleviating HFSR severity in patients with cancer treated with VEGFR-TKIs. None disclosed. CorrectionJournal of the American Academy of DermatologyPreviewHuang WK, Hsu HC, Yang TS, Lu CW, Pan YR, Wu CE, Chung WH, Hung SI, Yeh CN. Zinc supplementation decreased incidence of grade ≥2 hand-foot skin reaction induced by regorafenib: A phase II randomized clinical trial. J Am Acad Dermatol. 2024:90(2):368-369 Full-Text PDF